ErbB tyrosine kinase receptor inhibitors in breast cancer treatment

The ErbB tyrosine kinase receptor family comprises 4 receptors (HER1 [EGFR/ErbB1], HER2 [ErbB2], HER3 [ErbB3] and HER4 [ErbB4]), and at least 10 ligands. Pre-clinical and clincial studies have indicated that members of this family have important roles in breast cancer development and progression, and which leads to the concept of targeting ErbB receptors as a promising treatment strategy. Trastuzumab, an anti-HER2 antibody, provided the first definitive evidence for the clinical efficacy of targeting an ErbB receptor in patients with breast cancer. Over the past 5 years, much interest has been generated as a result of the development of orally-administered ErbB tyrosine kinase receptor inhibitors. Pre-clinical and early clinical studies with these agents are reviewed here.     

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutations are well-described drivers of non-small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors (TKIs) have become key components of the NSCLC front-line treatment landscape. Tumors inevitably develop resistance to these agents, and development efforts continue to focus on identifying mechanisms of resistance and drugs to target these mechanisms.

Areas covered: With several EGFR TKIs approved for use in the first-line or in later-line settings, an understanding of the efficacy and safety of these inhibitors in various populations is warranted. Furthermore, given the frequent emergence of drug resistance in NSCLC, examination of tumor tissue throughout the disease course provides the opportunity to select treatments based on the tumor’s mutation profile. Here, we discuss: key efficacy and safety findings for approved and investigational EGFR TKIs; known mechanisms of resistance, particularly the T790M acquired EGFR mutation; and recent advances in EGFR mutational testing that may facilitate less invasive tissue testing and guide treatment selection.

Expert commentary: The expanding armamentarium of EGFR TKIs, improvements in the understanding of resistance mechanisms and technological developments in the molecular analysis of tumors may help render EGFR mutation-positive NSCLC a chronic disease in many patients by facilitating optimal sequential therapy.     

Role of small-molecule kit receptor tyrosine kinase inhibitors in the treatment of small-cell lung cancer

The prognosis of extensive-stage small-cell lung cancer (SCLC) has changed little in the past 3 decades, despite the documentation of high response rates to multiple chemotherapeutic regimens. Increasing the dose or the dose intensity of standard chemotherapy has increased toxicity without a significant improvement in outcome. However, our understanding of the biology of this disease has dramatically changed over the past 30 years, and this understanding has resulted in the identification of novel therapeutic targets. Evidence supporting the Kit growth factor receptor tyrosine kinase as a therapeutic target in SCLC is detailed. The properties of small-molecule Kit inhibitors currently in clinical development, as well as their efficacy in preclinical SCLC studies, are presented. The rationale for combining small-molecule Kit inhibitors with standard chemotherapy in clinical trials for extensive-stage SCLC is discussed.     

EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer

The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available standard therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in standard non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents in this setting. In recent years, however, several authors have reported a growing number of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest that a response can be obtained using EGFR TKI treatment for patients with BM, especially those harboring EGFR mutations.     

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.     

表皮生长因子受体酪氨酸激酶抑制剂联合化疗治疗肺癌的研究进展

表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(EGFR-TKI)对EGFR突变肺癌患者表现出很好的疗效,对于EGFR野生型肺癌患者化疗药物是首选,EGFR-TKI和化疗药物联合在基础研究方面表现出良好的协同作用,而在临床研究方面与其两药联合的时序有关.     

Comparative pre-clinical evaluation of receptor tyrosine kinase inhibitors for the treatment of multiple myeloma

Background

Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4;14) MM.

Methods

Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU-11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4;14)-positive and t(4;14)-negative human MM tumour xenograft models.

Results

PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI₅₀ = 10 nM and 730 nM, versus GI₅₀ >1 μM and 2.7 μM for parental cells; p < 0.0001) and t(4;14) positive MM cell lines (GI₅₀ = 4-10 μM and 1-3 μM, versus GI₅₀ = 14-15 μM and 4-5 μM for t(4;14) negative MM cells; p ≤ 0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4;14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4;14)-positive (PD174073 and sunitinib) but not a t(4;14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4;14)-negative model.

Conclusions

These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4;14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib.     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.     

The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer

The discovery of “driver” genomic alterations in patients with non‐small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First‐generation and second‐generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine‐to‐methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR‐mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third‐generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third‐generation agents in the treatment of patients with advanced NSCLC. Cancer 2015;121:E1–E6. © 2014 American Cancer Society.     

非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂的一线治疗

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)参与的晚期非小细胞肺癌(NSCLC)一线治疗的几种模式显示出不同的结果.化疗与EGFR-TKI联合未显示生存优势,化疗序贯EGFR-TKI和EGFR-TKI单药这两种模式取得了巨大的突破,为晚期NSCLC个体化治疗开辟了新的道路.同时发现EGFR突变在晚期NSCLC靶向治疗方面有很好的疗效预测价值.     

Role of tyrosine kinase inhibitors in the treatment of advanced colorectal cancer

Colorectal cancer (CRC) is a common health problem in Western countries. In advanced disease, either FOLFOX (oxaliplatin/5-fluorouracil [5-FU]/leucovorin [LV]) or FOLFIRI (irinotecan/LV/5-FU) are accepted first-line chemotherapy regimens, but median survival appears to plateau with a chemotherapy-only approach. The use of epidermal growth factor receptor (EGFR)- and vascular endothelial growth factor (VEGF)-targeting monoclonal antibodies has increased the median survival of patients with advanced CRC beyond 20 months. However, the precise role of cetuximab, panitumumab and bevacizumab in combination with different chemotherapeutic regimens is still being determined in first- and second-line settings. The activity and tolerance of the EGFR tyrosine kinase inhibitors (TKIs), gefitinib erlotinib, and EKB-569, alone or in combination with chemotherapy, have been explored in patients with metastatic CRC. Regarding VEGF receptor TKIs, 2 phase III clinical trials determined the role of vatalanib in combination with FOLFOX. Efficacy of the oral multitargeted TKIs sorafenib and sunitinib is under investigation. This article aims to review the role of TKIs in advanced CRC.     

表皮生长因子受体与酪氨酸激酶抑制剂在肿瘤防治中的应用进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)信号传递系统可调控细胞周期，调节细胞生长与分化，促进损伤修复。EGFR在包括非小细胞肺癌(non-small-cell lung cancer,NSCLC)在内的多种上皮源性肿瘤中过表达预示存活率低、预后差、转移可能性大，可作为肿瘤基因治疗的靶位。酪氨酸激酶抑制剂(tyrosine kinase inhibitors，TKIs)可选择性抑制EGFR酪氨酸激酶活性，抑制肿瘤生长，增加放化疗敏感性。     

Epidermal growth factor receptor tyrosine kinase inhibitors

Activation of the epidermal growth factor receptor (EGFR) has been linked to tumour proliferation, invasion, metastasis and angiogenesis in epithelial tumours. Inhibitors of the EGFR have emerged as promising anticancer agents and two main approaches have been developed, humanised monoclonal antibodies and tyrosine kinase inhibitors. This review discusses the current status of EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have entered clinical development. EGFR-TKIs are generally well tolerated and can sometimes produce impressive tumour regression in patients with advanced non-small-cell lung cancer. However, highly predictive or surrogate markers of activity have not been identified and there remains a need for translational research in their future development.     

mTOR kinase inhibitors as potential cancer therapeutic drugs

The mammalian target of rapamycin (mTOR) plays a critical role in the positive regulation of cell growth and survival primarily through direct interaction with raptor (forming mTORC complex 1; mTORC1) or rictor (forming mTOR complex 2; mTORC2). The mTOR axis is often activated in many types of cancer and thus has become an attractive cancer therapeutic target. The modest clinical anticancer activity of conventional mTOR allosteric inhibitors, rapamycin and its analogs (rapalogs), which preferentially inhibit mTORC1, in most types of cancer, has encouraged great efforts to develop mTOR kinase inhibitors (TORKinibs) that inhibit both mTORC1 and mTORC2, in the hope of developing a novel generation of mTOR inhibitors with better therapeutic efficacy than rapalogs. Several TORKinibs have been developed and actively studied pre-clinically and clinically. This review will highlight recent advances in the development and research of TORKinibs and discuss some potential issues or challenges in this area.     

mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt

Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.     

Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells

Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl.     

Small molecule epidermal growth factor receptor tyrosine kinase inhibitors: an overview

The epidermal growth factor receptor (EGFR) has been identified as a relevant target for treatment of solid tumors, as it is involved in regulating cellular functions important in the proliferation and survival of cancer cells, is commonly expressed in a range of tumors, and high expression is often related to poor prognosis. Some of the most advanced target based agents in clinical development are the EGFR tyrosine kinase inhibitors (EGFR-TKIs). This brief review summarizes the results of phase II monotherapy trials of EGFR TKIs in cancer patients. The molecular mechanisms involved in regulating the sensitivity/resistance of tumor cells to EGFR-TKIs are also discussed.     

Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors

The growth and proliferation of cells are usually tightly regulated processes that are activated by stimuli from their environment. Epidermal growth factor (EGF)-related peptides represent a class of molecules that can trigger cell proliferation, among several cellular processes, such as differentiation, migration, and survival. Binding of EGF-like peptides to the EGF receptor (EGFR) at the cell surface leads to a cascade of intracellular reactions that transduce signals to the nucleus, resulting in particular gene expression patterns. However, in many tumor cells, the regulation of EGFR activity is lost, due to increased or aberrant expression of the receptor or its ligands, and this contributes to many processes important for tumor growth, including cell proliferation, survival, angiogenesis, invasion, and metastasis. Many strategies have been developed that specifically target the EGFR and inhibit its activity. Of these, small-molecule tyrosine kinase inhibitors represent one of the most promising classes of anticancer agents. Here, we describe the status of small-molecule EGFR tyrosine kinase inhibitors in preclinical and clinical development.